Zyloprim

SIDE EFFECTS

Data upon which the following estimates of incidence of adverse reactions are
made are derived from experiences reported in the literature, unpublished clinical
trials and voluntary reports since marketing of ZYLOPRIM (allopurinol) began.
Past experience suggested that the most frequent event following the initiation
of allopurinol treatment was an increase in acute attacks of gout (average 6%
in early studies). An analysis of current usage suggests that the incidence
of acute gouty attacks has diminished to less than 1%. The explanation for this
decrease has not been determined but may be due in part to initiating therapy
more gradually (see PRECAUTIONSandDOSAGE
AND ADMINISTRATION).

The most frequent adverse reaction to ZYLOPRIM (allopurinol) is skin rash. Skin reactions
can be severe and sometimes fatal. Therefore, treatment with ZYLOPRIM (allopurinol) should
be discontinued immediately if a rash develops (see WARNINGS). Some patients
with the most severe reaction also had fever, chills, arthralgias, cholestatic
jaundice, eosinophilia and mild leukocytosis or leukopenia. Among 55 patients
with gout treated with ZYLO-PRIM for 3 to 34 months (average greater than 1
year) and followed prospectively, Rundles observed that 3% of patients developed
a type of drug reaction which was predominantly a pru-ritic maculopapular skin
eruption, sometimes scaly or exfolia-tive. However, with current usage, skin
reactions have been observed less frequently than 1%. The explanation for this
decrease is not obvious. The incidence of skin rash may be increased in the
presence of renal insufficiency. The frequency of skin rash among patients receiving
ampicillin or amoxicillin concurrently with ZYLOPRIM (allopurinol) has been reported to be
increased (see PRECAUTIONS).

*Early clinical studies and incidence rates from early clinical experience
with ZYLOPRIM (allopurinol) suggested that these adverse reactions were found to occur at
a rate of greater than 1%. The most frequent event observed was acute attacks
of gout following the initiation of therapy. Analyses of current usage suggest
that the incidence of these adverse reactions is now less than 1%. The explanation
for this decrease has not been determined, but it may be due to following recommended
usage (see ADVERSE REACTIONS introduction, INDICATIONS
AND USAGE, PRECAUTIONS, andDOSAGE
AND ADMINISTRATION).

DRUG INTERACTIONS

In patients receiving mercaptopurine or IMU-RAN (azathioprine), the concomitant
administration of 300 to 600 mg of ZYLOPRIM (allopurinol) per day will require a reduction
in dose to approximately one third to one fourth of the usual dose of mercaptopurine
or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine
should be made on the basis of therapeutic response and the appearance of toxic
effects (see CLINICAL PHARMACOLOGY).

It has been reported that ZYLOPRIM (allopurinol) prolongs the half-life of the anticoagulant, dicumarol. The clinical basis of this drug interaction has not been established but should be noted when ZYLOPRIM (allopurinol) is given to patients already on dicumarol therapy.

Since the excretion of oxipurinol is similar to that of urate, uricosuric agents,
which increase the excretion of urate, are also likely to increase the excretion
of oxipurinol and thus lower the degree of inhibition of xanthine oxidase. The
concomitant administration of uricosuric agents and ZYLOPRIM (allopurinol) has been associated
with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and
an increase in urinaryuric acid excretion compared with that observed with
ZYLOPRIM (allopurinol) alone. Although clinical evidence to date has not demonstrated renal
precipitation of oxypurines in patients either on ZYLO-PRIM alone or in combination
with uricosuric agents, the possibility should be kept in mind.

The reports that the concomitant use of ZYLOPRIM (allopurinol) and thi-azide diuretics may
contribute to the enhancement of allopuri-nol toxicity in some patients have
been reviewed in an attempt to establish a cause-and-effect relationship and
a mechanism of causation. Review of these case reports indicates that the patients
were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were
not often performed. In those patients in whom renal insufficiency was documented,
however, the recommendation to lower the dose of ZYLOPRIM (allopurinol) was not followed.
Although a causal mechanism and a cause-and-effect relationship have not been
established, current evidence suggests that renal function should be monitored
in patients on thi-azide diuretics and ZYLOPRIM (allopurinol) even in the absence of renal
failure, and dosage levels should be even more conservatively adjusted in those
patients on such combined therapy if diminished renal function is detected.

An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with ZYLOPRIM (allopurinol) compared to patients who are not receiving both drugs. The cause of the reported association has not been established.

Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of ZYLOPRIM (allopurinol) . However, in a well-controlled study of patients with lymphoma on combination therapy, ZYLOPRIM (allopurinol) did not increase the marrow toxicity of patients treated with cyclophos-phamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.

Tolbutamide's conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver. The clinical significance, if any, of these observations is unknown.

Chlorpropamide's plasma half-life may be prolonged by ZYLOPRIM (allopurinol) , since ZYLOPRIM (allopurinol) and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if ZYLOPRIM (allopurinol) and chlorpropamide are given concomitantly in the presence of renal insufficiency.

Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with ZYLOPRIM (allopurinol) . Monitoring of cyclosporine levels and possible adjustment of cyclo-sporine dosage should be considered when these drugs are co-administered.

Drug/Laboratory Test Interactions: ZYLOPRIM (allopurinol) is not known to alter the
accuracy of laboratory tests.